Cost-Effectiveness Analysis of Topiramate versus Phenobarbital in the Treatment of Children with Febrile Seizure.

Objectives Febrile seizure is common disorder in childhood, with a prevalence of 2% to 5%. There are many drugs for treatment of this disease; however, the most common prescribed medication in Iran is phenobarbital that is cheap, but it has many side effects. We aimed to compare the cost-effectiveness of topiramate versus phenobarbital in patients with febrile seizure in the south of Iran. Materials & Methods This econometric cost-effectiveness and cost-utility study were conducted on 91 patients with febrile seizure to assess two strategies of oral drug therapy including phenobarbital and topiramate in 2016-2017. Of all, 51 patients were treated with phenobarbital and 40 patients received topiramate. We followed up the patients for six months, using a randomized and single-blinded approach. A decision tree model was used. The outcomes of the model included febrile seizure and utility. The study was conducted from the perspective of the community; therefore, direct and indirect costs were included in the study. Excel and Tree Age software (2011) were used to analyze the results. Results Topiramate was cheaper and more effective than phenobarbital. In patients in the phenobarbital and topiramate groups, the mean costs were $740 and $674 per PPP, utility scores were 0.72 and 0.82, and febrile seizure without side effects were 0.3 and 0.6, respectively. Moreover, one-way sensitivity analysis confirmed the robustness of the results of the study. Conclusion Topiramate in patients with febrile seizure is a fully cost-effective and cost-efficient strategy suggested as a better alternative for children with febrile seizure.


Introduction
In childhood, febrile seizures are the most prevalent seizures (1). The prevalence of this disease in most parts of the world is 2% to 5%, and 1% to 6% of people with epilepsy have a history of febrile seizure (2). The disease is generally of two types, simple and complex. About 65% to 90% of the febrile seizures are simple (3). If one has a family history of febrile seizure, he/she will be 31% more likely than others to develop the disease, and family history seems to have a significant effect on febrile seizure (4). The prevalence of febrile seizure (in particular, complex febrile seizure) has increased over the past decade (5).
No treatment is required for febrile seizure occurring once or twice, but it needs medications if repeated. Febrile seizure that lasts for more than five minutes requires treatment and medications, but in 30% of cases, the drugs have probable side effects (6). The occurrence of this disease can have a great impact on the parents and cause anxiety and tensions in the family (7). The pathophysiology of this disease is unknown and both genetic factors and environment can affect the disease (8). The prognosis of this disease is good and in some cases, it may progress to epilepsy (9,10). The disease requires prolonged therapeutic courses and the treatment of patients with febrile seizure and epilepsy usually lasts for a long period. In addition, the drugs used for the treatment can cause many side effects and these side effects have a great impact on the patient's quality of life, and the patient has to incur lots of costs to treat these side effects (11). Therefore, it seems reasonable to avoid the repetition of febrile seizure as far as possible using safe methods (12).
Many drugs are prescribed for patients with febrile seizure and epilepsy, but because of the differences in the costs, effectiveness, and side effects, there are controversies over selecting the best drug to be prescribed (13). Phenobarbital is one of the drugs commonly prescribed in Iran. Phenobarbital is a drug used orally and intravenously to treat patients with this disease (14). Topiramate is another drug widely used in the world to treat local and general seizure (15). However, both topiramate and phenobarbital have side effects. Side effects of phenobarbital include behavioral problems, sleepiness, acne, and cognitive problems (16), and those of topiramate include weakness, sleepiness, lack of speech, depression, depression problems, hallucinations, imbalance, dizziness, numbness, headache, diarrhea, nausea, anorexia, speech impairment, sweating, kidney stones, infection, and fever (17)(18)(19)(20). It seems reasonable to prevent the recurrence of febrile seizure, as far as possible, using safe methods. Nonetheless, there is no therapeutic regimen accepted by all experts. In addition, there are controversies over the efficacy and side effects of these drugs, and there are uncertainties over choosing the best drug to be prescribed by physicians (21).
Policymakers will never have enough money to do whatever they want, it is not enough to know all the existing interventions to solve a health problem; hence, they also need to be aware of the costs of interventions (22  Our studied subjects included children who had more than two cases of complex febrile seizure or simple febrile seizure diagnosed by a pediatric neurologist. Considering the research objectives and community size, we used the census method to select the samples. Since topiramate was not familiar for these patients in Iran and was more commonly prescribed for patients with epilepsy, first, the drug was introduced to the parents of the patients and written consent forms were obtained from those who were willing to participate in the study. If not willing to participate in the study, they were allowed to withdraw from the study. The samples were divided into two groups, A and B.
Then, a type of these drugs was prescribed for each group of patients. The patients were selected quite randomly through randomized block permutation design. The researcher made telephone calls to the parents of the patients, collected data, and completed the cost and effectiveness checklist for each drug.

Inclusion and Exclusion Criteria
The inclusion criteria were as follows: Age 6 Iran J Child Neurol. Autumn 2019 Vol. 13 No. 4 months to 60 months, no history of afebrile seizure without fever, three times or more simple febrile seizure or complex seizure; lack of Central Nervous System (CNS) infection and without Electrolyte Imbalance. The exclusion criteria were change in the diagnosis of the disorder; resulting in continuation of another drug for the child; quitting treatment due to the occurrence of drug side effect.

Clinical inputs
To compare the efficacy of the drugs, we used the following clinical outcomes: lack of recurrent febrile seizure and utility. They were investigated through administering the drugs and following up the patients for six months. To determine the amount of success and failure of each drug in controlling the febrile seizure, the number of patients with febrile seizure was divided by the total number of patients in each group. Moreover, utility scores were obtained using EQ-5D questionnaire and patient interviews.

Treatment Costs
Data on direct medical costs were collected from outpatient medical records, as well as self-reports by the experts in the field. Data on direct nonmedical costs and indirect costs were collected based on self-reports by the patients through faceto-face interviews or telephone calls.

Results
Overall, 91 patients less than five years of age with febrile seizure were enrolled. and had a better level of utility than phenobarbital.
Thus, it is more preferable than phenobarbital.

Uncertainty analysis
The effects of uncertainty were studied using oneway sensitivity analysis and the values of each variable changed by 20% plotted in the form of a tornado diagram.

Discussion
The aim of this study was to evaluate the costeffectiveness of phenobarbital and topiramate drugs in patients with febrile seizure. Phenobarbital is commonly prescribed in Iran for children with febrile seizure, but in our county, topiramate is not prescribed for children with febrile seizure and is only prescribed for epileptic patients. However, the pilot administration of topiramate for children with febrile seizure has recently been started. The aim of this study was to examine the cost-effectiveness of these two drugs in order to choose the best treatment.
Since no specific study has been conducted on febrile seizure so far, we have compared our findings with the results of the studies conducted on patients with epilepsy, which is a long-term, progressive, and persistent type of febrile seizure.
Most drugs used for patients with epilepsy are similar to those used for treating febrile seizure (25).
In comparison with phenobarbital, topiramate was a better option in terms of both cost-effectiveness and cost-utility. As to the lack of recurrence of febrile seizure in both groups, the results of ICER showed that among treatment strategies in the country, topiramate was a superior and costeffective option because of its higher efficacy and lower costs than phenobarbital. The results of this study are consistent with those of a study (26) suggesting topiramate was a cost-effective drug.
Moreover, as to the utility outcome in both groups, Furthermore, the results of one-way sensitivity analysis showed that the incremental costeffectiveness ratio had the highest level of sensitivity to the "utility of patients who consumed topiramate", and incremental cost-effectiveness ratio had the highest level of sensitivity to "the cost spent by patients who consumed phenobarbital".
In both cases, the ICER value was negative; it is possible to make definite conclusions about the results of the study. Therefore, sensitivity analysis did not change the status of topiramate as the most effective drug; it is a sign of the robustness of the results of the study. Therefore, the results of the present study are consistent with other findings (26,27).
The results of this study showed that when the outcomes of the econometric evaluation are utility and the lack of recurrent febrile seizure in children with the disease, topiramate drug is more costeffective than the phenobarbital and it is more cost-effective, favorable, and the dominant option because phenobarbital has a higher expected cost and a lower efficacy and lower utility than topiramate.
Among the strengths of this study, we can mention the followings: inclusion of all costs, including direct medical and non-medical costs, as well as indirect costs in the model, and the use of regional data on costs and effectiveness collected from the self-reports of the patients.

Limitations
The study had some limitations.